Vancomycin, enterococci resistant structure

The prototypical lantibiotic, nisin, was discovered in 1928 for its antibacterial properties and has been used as a preservative in dairy products since the 1950s (1). Nisin and other lantibiotics exhibit nanomolar efficacy against many Gram-positive strains of bacteria (2), which include methicillin resistant Staphylococcus aureus, vancomycin resistant enterococci, and oxacillin resistant bacteria. On the other hand, some lantibiotics function as morphogenetic peptides rather than antibiotics and are important for spore formation in streptomycetes (3). Since the structural elucidation of nisin in the early 1970s, extensive research efforts have been directed at understanding the biosynthesis and mode of action of various lantibiotics. 

Linezolid is FDA approved for treatment of infections caused by vancomycin-resistant E. faecium nosocomial pneumonia caused by methicillin-susceptible and methicillin-resistant strains of S. aureus community-acquired pneumonia caused by penicillin-susceptible strains of S. pneumoniae complicated skin and skin-structure infections caused by streptococci and methicillin-susceptible and -resistant strains of S. aureus and uncomplicated skin and skin-structure infections. In noncomparative studies, linezolid (600 mg twice daily) has had clinical and miaobiological cure rates in the range of 85 to 90% in treatment of a variety of infections (soft tissue, urinary tract, and bacteremia) caused by vancomycin-resistant E. faecium. A 200-mg, twice-daily dose was less effective, with clinical and microbiological cure rates of approximately 75 and 59%, respectively. The 600-mg, twice-daily dose, therefore, should be used for treatment of infections caused by enterococci. A 400-mg, twice-daily dosage regimen is recommended only for treatment of uncomplicated skin and skin-structure infections. 

Cure rates with linezolid ( 60%) were similar to those with vancomycin for nosocomial pneumonia caused by methicillin-resistant or -susceptible S. aureus. Linezolid efficacy also was similar to that of either oxacillin or vancomycin for skin arul skin-structure infections, the majority of cases due to by 8. aureus. Linezolid appears comparable in efficacy to varwomycin for methicillin-resistant strains. Linezolid may be effective for patients with methicillin-resistant S. aureus infections who are failing varwomycin therapy or whose isolates have reduced susceptibility to vancomycin. Linezolid is bacteriostatic for staphylococci arul enterococci arul probably should not be used to treat suspected erulocarditis. 

VanX is a carboxypeptidase that hydrolyzes the amide bond of a dipeptide, D-alanyl-D-alanine (D-Ala-D-Ala). This enzyme is essential for vancomycin-resistant enterococci (VRE), because it produces peptidoglycan precursors terminating in D-alanyl-D-lactate (D-Ala-D-Lac) in place of D-Ala-D-Ala, resulting in a 100-fold decrease in the affinity with vancomycin.Scheme 5 depicts a proposed mechanism of VanX, where the active-site structure is similar to those of CPDA and thermolysin. The Zn -bound H2O activated by Glul81 attacks... 

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